Mechanistically Linking Insulin Action and the Thermic Effect of Food

胰岛素作用与食物热效应的机制联系

• 批准号: 9769720
• 负责人: Don Tianmu Li
• 金额: $ 5万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-16 至 2020-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769720
• 关键词: 3T3-L1 Cells; Adipose tissue; Adrenergic Agents; Adult; Affect; Age; Aging; Binding; Biological Assay; C-terminal; Cell Line; Cell Nucleus; Cells; Central obesity; ChIP-seq; Chimeric Proteins; Cost of Illness; DNA; Data; Deposition; Development; Diabetes Mellitus; Disease; Energy Metabolism; Exhibits; Fatty acid glycerol esters; Food; Futile Cycling; Gene Expression; Genes; Genetic Transcription; Goals; Half-Life; Healthcare Systems; Hypertension; Immunofluorescence Immunologic; In Vitro; Insulin; Insulin Resistance; Intake; Intervention; Knock-out; Knockout Mice; Knowledge; Learning; Light; Link; Luciferases; Mediating; Metabolic; Metabolic syndrome; Mitochondria; Modeling; Molecular; Morbidity - disease rate; Mouse Cell Line; Mouse Strains; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutrient; Obesity; Oxygen Consumption; Pathogenesis; Pathway interactions; Pharmacology; Physicians; Play; Process; Proteins; Regulation; Regulatory Pathway; Research; Response Elements; Role; Sarcoplasmic Reticulum; Scientist; Signal Transduction; Site; Small Interfering RNA; Testing; Thermogenesis; Time; Tissues; Training; Transgenic Mice; Transgenic Organisms; United States; Vasopressins; Work; basal insulin; base; clinically relevant; cost; diabetes mellitus therapy; energy balance; experience; glucose uptake; in vivo; insulin signaling; mouse model; novel; obesity prevention; total energy expenditure; transcriptome; transcriptome sequencing

Project Summary: Mechanistically Linking Insulin Action and the Thermic Effect of Food Positive energy balance leading to ectopic fat deposition has been shown to play a major role in the pathogenesis of insulin resistance and type 2 diabetes, a disease that costs the United States healthcare system over 300 billion dollars a year. One important component of energy expenditure is the thermic effect of food (TEF), which represents the increase in heat production and oxygen consumption following nutrient intake. However, the mechanistic link between nutrient intake and energy expenditure remains poorly understood. Insulin stimulated cleavage of the TUG protein has been shown to regulate glucose uptake and vasopressin inactivation in vitro and in vivo. Unexpectedly, mice with constitutive and unregulated cleavage of TUG proteins exhibit significantly increased energy expenditure that is associated with transcriptional induction of proteins that mediate futile cycles of metabolic substrates. Conversely, mice with muscle specific deletion of TUG have decreased expression of thermogenic proteins. This proposal will test the hypothesis that the TUG C-terminal cleavage product regulates energy expenditure by localizing to the nucleus and modulating gene expression. The first aim is to study the mechanism of increased energy expenditure in transgenic mice with constitutive TUG cleavage. The dynamics of TUG C-terminal product localization and how it is affected in insulin resistant tissues will be studied in complementary mouse strains. Interaction partners of the TUG C-terminus within the nucleus will be identified using unbiased screens and verified in both mice and cell lines. The second aim is to understand how degradation of the TUG C-terminus is regulated by the N-end rule, which is well described to regulate the half-life of cleavage products. Tagged fusion proteins, siRNA, and in vivo characterization will be used to determine how the abundance of TUG may be regulated. Overall, this proposal will elucidate a novel link between insulin signaling and energy expenditure and provide the groundwork for further studies on how this process may be regulated. Such studies will also allow for the identification of potential sites of pharmacologic intervention. Finally, the proposal includes a comprehensive training plan that will provide important new learning experiences to support the applicant’s development as a physician-scientist who is able to integrate scientific work and knowledge of diabetes with novel clinically relevant research.

项目摘要：胰岛素作用与食物热效应的机械联系 正能量平衡导致异位脂肪沉积已被证明在发病机制中起主要作用 胰岛素抵抗和2型糖尿病，一种花费美国医疗保健系统超过3000亿美元的疾病， 美元一年。能量消耗的一个重要组成部分是食物的热效应（TEF）， 表示摄入营养物后产热和耗氧量的增加。但 营养摄入和能量消耗之间的机械联系仍然知之甚少。胰岛素刺激 TUG蛋白的切割已显示在体外调节葡萄糖摄取和加压素失活， in vivo.出乎意料的是，具有TUG蛋白的组成型和不受调节的切割的小鼠表现出显著的 与介导无效循环的蛋白质的转录诱导相关的能量消耗增加 代谢底物。相反，肌肉特异性TUG缺失的小鼠， 产热蛋白该提案将检验TUG C-末端切割产物调节 通过定位于细胞核和调节基因表达来调节能量消耗。第一个目标是研究 具有组成性TUG切割的转基因小鼠中能量消耗增加的机制。的动态 TUG C-末端产物定位及其在胰岛素抵抗组织中的影响将在 互补小鼠品系。将鉴定TUG C-末端在细胞核内的相互作用伴侣 使用无偏筛选并在小鼠和细胞系中验证。第二个目标是了解退化 TUG C-末端的N-末端规则调节，该规则被充分描述为调节切割的半衰期 产品.标记的融合蛋白，siRNA和体内表征将用于确定如何在细胞内表达。 可以调节TUG的丰度。总的来说，这个提议将阐明胰岛素信号传导之间的一种新的联系， 和能量消耗，并为进一步研究如何调节这一过程提供基础。 这些研究还将允许确定潜在的药理学干预部位。最后 建议包括一个全面的培训计划，将提供重要的新的学习经验，以支持 申请人作为一名能够整合科学工作和知识的医生科学家的发展 糖尿病与新的临床相关研究。